Basic Surgery (100q).1

Although peripheral access can be used for intravenous nutrition, the major disadvantage of this technique is limited caloric delivery to meet catabolic demands within tolerated fluid limits. Infusion of glucose (up to 10%), amino acid solutions, and fat emulsions can be administered peripherally but these solutions must be nearly isotonic to avoid peripheral vein sclerosis. The preferred method of access for total parenteral nutrition is into the superior vena cava by cutaneous cannulation of the subclavian vein. Alternative sites include the internal and external jugular vein but the catheter exiting from the neck region makes it more difficult to secure and maintain a sterile dressing. Complications from long-term central venous catheterization include venous thrombosis and venous catheter-related infection. Thrombosis of central vessels is a complication which is often overlooked. The clinical suspicion of subclavian vein thrombosis is only about 3%, whereas studies that use phlebography or radionucleotide venography indicate the incidence is as high as 35%.

Phagocytosis is a specialized form of endocytosis by which large particles are internalized by specialized cells primarily macrophages and neutrophils. To be phagocytosed, particles must bind to the surface of the phagocytic cell, usually as the result of specific antibody coating the particle. The phagocytic cell then extends pseudopods which engulf the particle. This event is followed by membrane fusion and a pinching off. As opposed to endocytosis, this process does not involve the membrane protein, clathrin, but rather actin. A physiologically relevant site of phagocytosis is the thyroid gland, where thyroid follicular cells phagocytose and digest thyroglobulin from the lumen of the thyroid follicle, thereby releasing the thyroid hormones, thyroxine triiodothyronine.

Cytokines are soluble peptide molecules that are synthesized and secreted by a number of cell types in response to injury, inflammation, and infection. Cytokines, which include the interleukins, tumor necrosis factor, colony-stimulating factors, and the interferons, comprise only one category of inflammatory mediators involved in the host response. Endotoxin, complement fragments, eicosanoids, kinins, nitric oxide, oxidants, and PAF are noncytokine mediators that also have important roles in the systemic inflammatory response. IL-1 and TNF-a, like other cytokines, have multiple effects on target cells and potentiate the actions of other mediators to produce an amplified inflammatory response. TNF-a is thought to play a central role in the stress response, particularly in response to endotoxemia.

Neurogenic shock occurs when severe head injury, spinal cord injury, or pharmacologic sympathetic blockade leads to sympathetic denervation and loss of vasomotor tone. Both arteriolar and venous vessels dilate, causing reduced systemic vascular resistance and a great increase in venous capacitance. The patient's extremities appear warm and dry, in contrast to those of a patient in cardiogenic or hypovolemic shock. Tachycardia is frequently observed, though the classic description of neurogenic shock includes bradycardia and hypotension. Volume administration to fill the expanded intravascular compartment is the mainstay of treatment. The use of alpha-adrenergic agonist is infrequently necessary to treat neurogenic shock.

The use of modified amino acid solutions is based on the false neurotransmitter hypothesis of the cause of hepatic coma. According to this hypothesis, the imbalance between aromatic and branched-chain amino acids in the plasma results in abnormally high levels of the toxic aromatic amino acids in the brain, thus provoking hepatic encephalopathy. The use of modified amino acid mixtures, with glucose as the calorie base, has been associated in a number of studies with improvement in encephalopathy. Meta-analysis has concluded that the use of such solutions is indicated as therapy for hepatic encephalopathy but has been proposed only for hepatic encephalopathy complicating acute exacerbation of chronic liver disease. Although there are a few anecdotal reports of beneficial effects on hepatic encephalopathy of acute fulminant hepatitis, the use of such a solution has not been advocated, but such a modified solution is tolerated better than standard amino acid mixtures in patients requiring TPN. In some studies, particularly in complicated surgical cases, the use of a high–branched-chain, low–aromatic amino acid solution has been associated with lower mortality. These statements are true only for studies in which the modified solutions are given with hypertonic glucose as a calorie base. Studies in which lipid was the principal calorie source have not revealed such improvements in mortality. In recent studies, giving an aromatic amino acid–deficient, branched-chain amino acid–enriched solution to patients about to undergo resection of the liver has proved particularly efficacious in a group of patients with cirrhosis, decreasing morbidity and showing a trend toward decreased mortality.

Macrophages, endothelial cells, lymphocytes, and other cells secrete a large number of different compounds, termed cytokines, that are most probably evolved for the purpose of local intercellular and intracellular signaling. Cytokines frequently are secreted after initial lymphocyte or macrophage activation, and may act on the secreting cell itself (autocrine activation) or on other cells within the same local environment (paracrine activation) to cause increased secretion of the same cytokine or other cytokines, respectively. Some cytokines are produced by several cell types, and most produce a wide array of effects. The duality of the effects of the cytokine component of host defenses, exerting both salutatory and deleterious effects on the host, has become increasingly evident.

The evaluation of most patients scheduled for elective surgery who do not have a history of significant bleeding disorders is somewhat controversial. An adequate history and physical examination screen out most patients with bleeding problems. For patients who are scheduled to undergo a major surgical procedure, it is advisable to obtain a CBC and platelet count, as well as a PT and APTT level. This detects a large number of bleeding disorders but does not rule out all possible causes of perioperative bleeding. Studies of platelet aggregation are indicated only for patients who are suspected of having qualitative defects of platelet function (e.g., von Willebrand's disease).

Cardiogenic shock occurs when the heart fails to generate adequate cardiac output to maintain tissue perfusion. Intrinsic causes such as myocardial dysfunction secondary to coronary artery disease, or extrinsic causes such as pulmonary embolism, tension pneumothorax, and pericardial tamponade, may produce cardiogenic shock. Principles of treatment of cardiogenic shock are aimed at optimizing preload, cardiac contractility, and afterload. Preload is usually adequate or high in cardiogenic shock. Dobutamine is a useful inotropic agent, particularly when filling pressures are high, because of its mild vasodilatory effect, as well as its effect to enhance cardiac contractility. Afterload-reducing agents, such as sodium nitroprusside, may be beneficial in cardiogenic shock in the setting of elevated filling pressures, low cardiac output, and elevated systemic vascular resistance. Cardiac output may improve with use of afterload-reducing agents by decreasing myocardial wall tension and optimizing the myocardial oxygen supply-demand ratio. The intra-aortic balloon pump (IABP), by providing diastolic augmentation, reducing left ventricular afterload, and reducing myocardial oxygen consumption, is sometimes useful in the treatment of cardiogenic shock. The IABP is especially useful in low–cardiac output postcardiotomy patients, in patients awaiting revascularization, and in patients with acute myocardial infarction complicated by mitral insufficiency or ventricular septal defect. The pneumatic antishock garment (PASG), which causes an increase in systemic vascular resistance, is contraindicated in cardiogenic shock.

The relationships between oxygen consumption and oxygen delivery represent one of the most interesting regulation systems in homeostasis. First of all, if one of the three components of oxygen delivery is abnormal, endogenous mechanisms regulate the other two until normal oxygen delivery has been restored. The various combinations of compensatory mechanisms supply adequate oxygen for systemic metabolism through a wide range of variations in oxygen delivery. When there is a change in oxygen consumption, there is a proportionate change in oxygen delivery, which occurs almost immediately, mediated completely by a change in cardiac output. Conversely, a primary change in oxygen delivery is not followed by any change in oxygen consumption. The normal ratio of oxygen delivery to consumption is approximately 5:1.

Clinical evidence of congestive heart failure in a patient with 8.5 gm. per dl. hemoglobin concentration is a misleading sign. Evidence of congestive failure is ordinarily a major risk factor, but in this particular patient the anemia lends itself to correction by preoperative transfusion with packed red blood cells, and often it is found that congestive failure and the associated increased risks disappear when the hemoglobin concentration is returned to the 12 gm. per dl. or higher ratio. All other factors are overt signs of increased likelihood of a postoperative cardiac event, the most ominous being a myocardial infarction 4 months preoperatively or the presence of a harsh aortic systolic murmur suggesting the presence of aortic stenosis. Age over 70 years and the presence of premature atrial or ventricular contractions on the electrocardiogram are less strong determinants of a postoperative cardiac complication.

Although there are numerous dressing products commercially available at present, no treatment has been demonstrated to improve healing beyond that of standard treatment which adheres to basic principles. In the absence of large amounts of necrotic tissue, wound debridement does not need to be accomplished surgically. Simple water irrigation either with whirlpool or by water from a hand held shower spray can generate enough power to effectively debride most wounds. Frequent moist dressing changes can accomplish this as well, and in some cases, occlusive absorptive dressings can generate enough tissue proteases to effectively degrade proteins which the absorptive dressings remove. Deeper portions of a wound may accumulate exudate and bacteria. In such cases, water irrigation may be particularly useful. Commonly used agents such as hydrogen peroxide actually may be harmful to normal tissue and are weak oxidants and do a poor job of debriding. Enzymatic debriding agents can be effective when used properly. Most of the newer dressing products have been designed to be more absorptive and achieve moist healing without infection from excess exudate. However, it must be emphasized that as long as moist healing is achieved, there has been no evidence that one product is better than another.

Gallstones have been found to be very prevalent in patients with type II (non–insulin-dependent) diabetes mellitus, perhaps related to the dyslipoproteinemia in such patients. Although the complications of acute cholecystitis (infection, sepsis, gangrene of the gallbladder) are more common in diabetics, a decision-analysis study has shown that prophylactic cholecystectomy cannot be justified since the risk of morbidity and/or mortality from the cholecystectomy procedure is as great as that of complications or death from acute cholecystitis. Patients who become symptomatic should be promptly prepared and should undergo elective cholecystectomy, because an emergency operation in these patients with comorbid conditions, especially coronary artery disease, has substantial added mortality associated with it. There is no causal relationship between diabetes and pancreatic cancer.

Acute symptomatic hyponatremia is characterized by central nervous system signs of increased intracranial pressure. Changes in blood pressure and pulse are secondary to increased intracranial pressure. In the absence of hypovolemia, asymptomatic patients may be treated by restriction of water intake; however, in such patients, hyponatremia should be partially corrected by parenteral sodium administration. Rapid correction, particularly to hypernatremia, may lead to central pontine myelinolysis. Oliguric renal failure may rapidly develop in severe hyponatremia

The problem with the patient with cancer is a very vexing one. Clearly, one of the metabolic effects of cancer, cachexia, affects patients in the last quartile of their disease and makes such patients intolerant of chemotherapy, radiation therapy, and, in many cases, operative procedures. Total parenteral nutrition (TPN) has been proposed as a means of reversing cachexia and enabling patients to better tolerate surgery, chemotherapy, and radiation therapy. In experimental animals, it is clear that the provision of calories and protein, especially in excessive amounts, is associated with the more rapid growth of tumors and decreased survival, especially in the group that is overfed in the extreme. There is also evidence suggesting that overfeeding, or at least TPN, may result in increased growth (or at least change cell kinetics) in patients who are overnourished with TPN. Of the randomized prospective trials that have been carried out, no trial utilizing chemotherapy or radiation therapy has revealed a survival advantage for patients receiving TPN. Indeed, in Shamberger's study, there is a suggestion that the tumor-free interval following treatment of lymphoma may be shorter in patients receiving TPN. In patients undergoing surgery, however, especially those who are severely malnourished (as recently revealed in the VA study) or in patients with major procedures such as esophagogastrectomy (as in Muller's study), evidence suggests that TPN is beneficial. In a late follow-up in Muller's study, there was no apparent increase in recurrence, and the survival rate was the same, despite much higher mortality in the non-TPN group. This suggests that any improved survival following operation may have been offset by an increased late recurrence rate, although it is difficult to reach this conclusion. In summary, for patients with cancer TPN probably nourishes the tumor as well as the host. Nonetheless, in severely malnourished patients provision of TPN from 5 to 10 days preoperatively may increase survival and decrease morbidity. Overfeeding must be avoided. Future studies will undoubtedly reveal that there are certain nutrients that tumors require, which probably should be best avoided.

The genetic blueprint of an organism is carried in the nucleus of every cell, encoded by the sequence of four bases—adenine, guanine, cytosine and thymine, which together make up two long chains bound together by hydrogen bonds to form a DNA double helix. A gene is a segment of DNA that is transcribed into a corresponding RNA molecule that either codes for a protein or forms a structural RNA molecule. Genes are commonly between 10,000 and 100,000 base pairs in length and include, in addition to the coding sequence, flanking regions and intervening sequences, termed introns. Introns are removed from the primary RNA transcript by a process called splicing. The basic unit of information is the codon, a sequence of three bases or triplet. The four nucleotide bases arranged as triplets lead to 64 possible codons. Sixty-one of these code for amino acids and three are termination signals called stop codons.

The most common cause of fatalities related to transfusion reactions result from ABO-incompatible transfusion related to clerical error. Most such reactions occur if a type O person receives type A red cells owing to a clerical error that occurs either at the time the blood sample was drawn, during processing in the laboratory, or at the time a unit is administered. The importance of extremely careful labeling, transfer, and handling of specimens and of cross-matched blood products cannot be overemphasized. Allergic and other reactions are common but rarely fatal. The transmission of bacterial organisms (e.g., Staphylococcus aureus) has been reported especially with platelet concentrates maintained at or near room temperature. Fortunately, such reactions are rare.

Metabolic response to injury results in increased energy expenditure. If energy intake is less than expenditure, oxidation of body fat stores and erosion of lean body mass will occur with resultant loss of weight. When weight loss exceeds 10–15% of body weight, the complications of malnutrition interact with disease processes, with increased morbidity and mortality rates. The goal of nutritional support is maintenance of body cell mass and limitation of weight loss to less than 10% preinjury. The major impact of nutritional support in the trauma patient is to aid host defense. Under-nutrition may compromise the available host defense mechanism and may thus increase the likelihood of invasive sepsis, multiple organ system failure, and death. Resuscitation, oxygenation and arrest of hemorrhage are immediate priorities for survival. Nutritional support is an essential part of the metabolic care of the critically ill patient and should be instituted after resuscitation before significant weight loss occurs. The nutritional requirements of a trauma patient can be determined by determining basal metabolic rate with appropriate increases based on extent of injury and hospital activity. After initial determination of nitrogen requirements, caloric requirements should be distributed at a ratio of 70% as glucose and 30% as fat.

Humoral defenses consist of antibody (immunoglobulin; Ig) and complement. All Ig classes (IgM, IgG, IgA, IgE, IgD) and IgG subclasses are composed of one type (M, G, A, E, D) of heavy and one type (K and g ) of light protein chains that consist of several domains both structurally and functionally. Each Ig molecule contains one or more units that consist of two heavy and two light chains linked by disulfide bonds. The amino terminus of both heavy and light chains contain several hypervariable regions that fold in three dimensions to produce the antigen-binding site. The carboxyl terminus of the heavy chains contain regions that activate complement and bind Fc receptors, by which direct adherence to polymorphonuclear leukocytes and macrophages take place after antigen binding occurs.
Initially, antibody of the IgM class is produced in response to an antigenic stimulus. A second exposure to the same antigen, or a cross-reactive antigen, leads to the so-called second set response, in which antibody of the IgG class with two binding sites is produced more rapidly and in larger quantity compared to the initial IgM primary response. Immunoglobulin of the IgA class is secreted by gut-associated lymphoid tissue and is combined with secretory components of protein to form a dimer termed secretory IgA. This antibody acts at a variety of epithelial sites to prevent microbial adherence and invasion. IgD and IgE exist in smaller amounts in the circulation and do not appear to play a major role as host defense components.

Treatment of pulmonary edema has two important goals, the first is to improve oxygenation if it is impaired, and the second is to minimize fibrosis and bacterial infection, which often accompany pulmonary edema caused by capillary injury. The treatment of interstitial edema is to maintain the hydrostatic pressure as low as compatible with adequate cardiac output and to raise the oncotic pressure selectively in the vascular space. These measures, combined with fluid restriction and diuresis, will decrease the amount of pulmonary edema. Since it is desirable to maintain filling pressures of the left ventricle as low as possible while maintaining a good cardiac output, inotropic drugs to improve left ventricular contractility are helpful. Isoproterenol or dopamine should be used, with serial cardiac output and filling pressure measurements. The first step in decreasing pulmonary edema is to decrease the pulmonary capillary hydrostatic pressure as low as is compatible with an adequate cardiac output. This is done by diuresis and fluid restriction. As the patient falls behind in blood volume, signs of hypovolemia may appear. Blood volume is then replenished with a fluid that stays in the vascular space. Packed red cells are ideal for this application. When the hematocrit is normal, concentrated salt-poor albumin should be used. This hyperoncotic fluid replenishes the blood volume by attracting interstitial fluid from throughout the body into the vascular space and supplements diuresis. This technique is useful even in the septic patient who may have increased capillary permeability and may loose albumin from the vascular space at a rapid rate. Even if albumin “leaks out”, the short term effects of expanding blood volume and decrease in edema will appear.

Collagen synthesis, an integral part of wound healing, is affected by many local and systemic factors. Protein depletion impairs fibroplasia. Hypoproteinemia leads to diminution of fibroblast proliferation, proteoglycan and collagen synthesis, angiogenesis, and wound remodeling. Although anemia was once believed to be a significant cause of wound disruption, studies have shown that, in the absence of malnutrition or hypovolemia, anemia with a hematocrit greater than 15% does not interfere with wound healing. In contrast, molecular oxygen is critical for collagen synthesis because it is one of the factors required for the hydroxylation of lysine and proline. Also, hypoxia favors wound infection. The role of age in collagen synthesis is not clear, but the incidence of wound failure and incisional hernias is greater in patients older than 60. Fibroplasia occurs at a slower rate in older animals. Perhaps more than any other factor, wound infection is associated with the risk of wound failure.

The survival of the cell requires that cytosolic composition be maintained within narrow limits, despite the constant influx of nutrients and the simultaneous outflow of waste. A familiar example of the distribution of ions across the cell membrane is that of sodium and potassium. Cells are typically rich in potassium and contain very little sodium. Despite the fact that they are constantly bathed by fluid that is precisely the opposite composition. Even more impressive is the distribution of ionized calcium. The extracellular concentration of this ion is typically of the order of 10–3M, whereas that of cytosol is typically 10–7M, a 10,000-fold gradient. Such nonequilibrium ion distributions are even more remarkable in light of the fact that the plasma membrane is, to varying degrees, leaky to ions such as sodium, potassium and calcium. The plasma membrane is leaky to a variety of substances, but it exhibits an astonishing ability to discriminate or select one substance over another. This selectivity relates to not only ions but also for organic compounds such as glucose. Finally, the selectivity of biologic membranes can be altered drastically as a result of regulatory or signaling processes that occur within the cell.

Fibrinolytic therapy induces a hemostatic defect through a combination of factors. Hypofibrinogenemia and fibrin degradation products inhibit fibrin polymerization and, in combination with a decrease in the clotting factors V and VIII, prolong the ability of blood to clot. However, coagulation tests in general do not correlate well with bleeding complications. A level of fibrinogen less than 100 mg/dl is associated with an increased risk of bleeding. Absolute contraindications to thrombolytic therapy include active internal bleeding, recent (less than 2 months) cerebral vascular accident, and documented left heart thrombosis. Recent (less than 10 days) major surgery, obstetric delivery, organ biopsy, or major trauma is considered a major relative contraindication to either regional or systemic thrombolytic therapy.

Intravenous administration of an antibiotic is clearly indicated for patients undergoing clean contaminated operations. These antibiotics should be administered prior to surgery to obtain adequate tissue levels at the time of potential contamination. However, there has been no added benefit demonstrated for the postoperative use of antibiotics with regard to prophylaxis. The choice of antibiotic is a complex issue which remains unresolved largely because both superficial and deep wound infections can occur as a result of either or both skin (superficial wound) flora (e.g., Staphylococcus aureus) and body site (deep wound) infection. For this reason, the administration of agents which possess activity directed against these expected agents is reasonable. Although administration of a first-generation cephalosporin is acceptable, second-generation cephalosporins or extended-spectrum penicillins with gram-positive and gram-negative activity and biliary tract excretion may be more suitable for patients undergoing gastrointestinal or biliary tract procedures. Similarly, the use of agents with additional anaerobic activity for patients undergoing gastrointestinal procedures involving the small bowel or colon should be considered. The administration of broad-spectrum agents such as third-generation cephalosporins for prophylaxis does not seem to provide additional benefit in comparison to the above-mentioned type antibiotics and may foster the development of resistant organisms within a given institution or superinfection within a given patient. There is evidence that in some cases the topical use of antimicrobial agents is equivalent to the administration of intravenous antimicrobial agent antibiotics.

True keloids are uncommon and occur predominantly in dark skinned people with a genetic predisposition for keloid formation. In most cases, the gene appears to be transmitted as an autosomal dominant pattern. The primary difference between a keloid and a hypertrophic scar is that a keloid extends beyond the boundary of the original tissue injury. It behaves as a tumor and extends into or invades the normal surrounding tissue creating a scar that is larger than the original wound. Histologically, keloids and hypertrophic scars are similar. Both contain an overabundance of collagen. Although the absolute number of fibroblasts is not increased, the production of collagen continually out paces the activity of collagenase, resulting in a scar of ever increasing dimensions. Hypertrophic scars respect the boundaries of the original injury and do not extend into normal unwounded tissue. There is less of a genetic predisposition, but hypertrophic scars also occur more frequently in Orientals and the Black population. They are often seen on the upper torso and across flexor surfaces. Some improvement in a keloid can be obtained with excision followed by intra-lesional steroid injection. However, the resulting scar is unpredictable and potentially worse. Reexcision and closure should, however, be considered for hypertrophic scars, if the condition of closure can be improved. This is especially pertinent for wounds that originally healed by secondary intention or that are complicated by infection. Keloids typically develop several months after the injury and rarely, if ever, subside. Hypertrophic scars usually develop within the first month after wounding and often subside gradually.

Intensive insulin therapy is indicated in patients with IDDM who can actively participate in their own management and the attainment of the goals set for their blood glucose and glycosylated hemoglobin (HgA1 c) levels. Because the main complication of intensive therapy is iatrogenic hypoglycemia, this mode of treatment is not indicated for patients with NIDDM, who often have coexisting medical conditions such as coronary artery disease and who tolerate hypoglycemia poorly. There is little or no evidence that macrovascular disease is affected by intensive insulin therapy, and the added weight gain and hyperinsulinemia associated with the therapy may worsen atherosclerosis. Unawareness of hypoglycemia is directly related to a recent hypoglycemia episode, so patients treated intensively are often unaware of the problem. Intensive therapy does not improve established retinopathy or nephropathy but slows or prevents progression of these complications; however, better glucose control may improve peripheral neuropathy.

Most patients undergoing elective operations are adequately nourished. Unless the patient has suffered significant preoperative malnutrition, characterized by weight loss greater than 10–15%, or has major intraoperative or postoperative complications, solutions containing 5% dextrose may be administered for five to seven days before initiation of enteral nutrition, with no detrimental effect on outcome. The usual postoperative surgical patient is given intravenous glucose at 125 cc/hour receives about 500 kcal/day, far less than the actual number of kcal needed to meet energy requirements. The increased cost of feedings and potential complications associated with intravenous nutrition cannot be justified. Although the use of jejunal feedings in the postoperative period may be useful in some patients, especially those undergoing extensive gastrointestinal surgery, this technique would not appear indicated in the patient described above.

The role of antibiotics in wound care is controversial. All open wounds are colonized with bacteria. Only when surrounding tissue is invaded (cellulitis) are systemic antibiotics clearly indicated. Antibiotics may also be useful in other situations such as when granulation tissue has a high bacterial count (> 105 organisms/gram tissue), or in the case of reduced resistance to bacteria such as in a diabetic foot ulcer. The routine use of systemic antibiotics for chronic wounds should be avoided to reduce the development of resistant bacterial strains within the wound. Topical ointments are frequently used and can be useful. The topical vehicle may help keep the wound moist and the bacterial count in the wound may be lowered as the result. However, as with most antibiotics, resistant organisms quickly emerge. Silver sulfadiazine, frequently used for burn care, is also useful for chronic wounds. Its broad spectrum of activity, lack of relevant drug-resistant plasmids in bacteria, and its low cost make it a good choice.

The clinical findings in sepsis and septic shock represent the host response to infection. Gram-positive and gram-negative bacteria, viruses, fungi, rickettsiae, and protozoa have all been reported to produce a clinical picture of septic shock, but the overall response is independent of the specific type of invading organism. Septic shock develops as a consequence of the combination metabolic and circulatory derangements accompanying the systemic infection. It appears that the circulatory deficits are preceded by the metabolic abnormalities induced by infection. In fact, the circulatory changes in hyperdynamic sepsis appear to be an adaptive response to the underlying metabolic dysfunction. Cardiac output is high and systemic vascular resistance low in hyperdynamic septic shock. However, splanchnic vasoconstriction is pronounced even in the absence of systemic hypotension and even though systemic vascular resistance is reduced. Expansion of circulating blood volume can occur through either transcapillary refill or fluid resuscitation. Due to the ongoing inflammatory mediator-induced increases in capillary permeability and continued loss of intravascular volume, exogenous volume resuscitation must be provided to restore venous return and ventricular filling.

Since protein is the functional and structural chemical of the body, most nutritional assessment techniques are estimates of protein reserves. The actual nitrogen balance can be measured by measuring the amount of nitrogen excreted. This is most conveniently done by measuring the amount of urea excreted in the urine, assuming that urea constitutes 85% of the total nitrogen excretion. Knowing nitrogen excretion, the amount of protein catabolized can be estimated and compared with the amount of protein ingested by the patient. Indirect assessments of protein reserves are based on single measurements of body substances that are dependent on rapid protein synthesis for maintenance of normal levels. Conventional serum proteins such as albumin and globulin are not affected by malnutrition until it is very severe. Proteins such as prealbumen and transferrin, which turn over more rapidly, are better indicators of protein status. Lymphocytes are rapidly destroyed and protein is required for the formation of new cells. Consequently, the absolute lymphocyte count is a useful measure of the status of protein reserves. The lymphocyte count is considered by some the best single “static” measurement characterizing nutritional status. Protein is also required for synthesizing the cells and mediators involved in skin test reactivity. Although skin test reactivity is a manifestation of lymphocyte-mediated immunity, its usefulness in patient assessment is probably that of assessment of the inflammatory response than lymphocyte activity per se. Some chronically and acutely malnourished patients convert from reactive to anergic, and reactivity can be restored by nutritional repletion.

Transcription of a gene begins at an initiation site associated with a specific DNA sequence, termed a promoter region. After binding to DNA, the RNA polymerase opens up a short region of the double helix to expose the nucleotides. Once the two strands of DNA are separated, the strand containing the promoter acts as a template to which ribonucleoside triphosphates base pair by hydrogen bonds. The initial products of transcription are known as heterogeneous nuclear RNA because of their large size variation. These primary transcripts are then processed to form mRNA. RNA splicing accounts for mature RNA being much shorter than nuclear RNA. Moreover, alternative splicing can lead to the production of different mRNA molecules and in some cases different proteins from the same gene. mRNA is exported from the nucleus only after processing is complete.

The planned surgical procedure is the major determining factor in assessing an individual patient's risk for perioperative complications and in deciding which anesthetic technique will be most appropriate. Good communication between the surgeon and the anesthesiologist is vital, as the surgeon knows better than anyone else the extent of the operation and the length of time it will require.

Epithelialization is more rapid under moist conditions than dry conditions. Without dressings, a superficial wound, or one with minimal devitalized tissue forms a scab or crust, meaning that the blood and serum will coagulate, dry, and form a protective moisture barrier over the open wound. If a wound is kept moist with an occlusive dressing, then epithelial migration is optimized. In addition, the pain of an open wound is dramatically reduced under an occlusive dressing. The traditional wet-to-dry dressing if truly left to dry, simply produces desiccation and necrosis of the surface layer of the wound which delays epithelialization. Although wet-to-dry dressings can be effective for debridement of wound exudate, they are generally less desirable than a moist healing environment combined with effective cleaning of the wound (i.e. water irrigation). Any open wound will leak plasma. With more inflammation, the plasma capillary permeability is further increased. This exudate of serum proteins and inflammatory cells serves as a rich culture medium. This, in turn, will continue to cycle bacterial proliferation and lead to further exudate formation. The net result of this cycle is delayed or absent wound healing. In addition, the edema that results from capillary dysfunction, increases the distance for diffusion from oxygen and nutrient sources to their metabolic targets.

Central in the general cardiovascular response to shock is the action of the heart itself. The principle determinants of cardiac function in the normal heart are the volume of blood available for the heart to pump (preload), the systolic contractile capability, and the diastolic filling of the ventricles. In hypovolemia, the two dynamic variables of cardiac function, ventricular filling and myocardial contractility remain paramount and determine the stroke volume. The product of stroke volume and heart rate in turn determines the cardiac output. Increases in ventricular end-diastolic volume, reflecting venous return, cause ventricular distention. Ventricular distention in turn produces increased volume output with each stroke, the Frank Starling mechanism. Contractile function may vary independent of volume status. Changes in the contractile function shift the Starling curve up and down, producing increases or decreases in stroke volume for any given end-diastolic volume. A fundamental requirement for cardiovascular function is adequate cardiac filling, and cardiac output cannot exceed venous return. The venous system contains nearly two-thirds of the total circulating blood volume, including 20% to 30% within the splanchnic venous system. Most of this volume resides in small veins, which comprise the bulk of venous capacitance. The venous system, especially that of the splanchnic circulation, becomes important in the physiologic compensation to hypoperfusion because it serves as a dynamic reservoir for the autoinfusion of blood volume involving both active and passive mechanisms. The splanchnic circulation makes major contributions to the maintenance of venous return, therefore, it is likely that sympathetic venoconstriction is responsible for a portion of the blood mobilized from the splanchnic venous circulation. Sympathetic mediated venoconstriction in skin and skeletal muscle is probably not as significant as a source of blood volume. Selective vasoconstriction occurs in response to alpha adrenergic receptor stimulation with increased sympathetic activity in shock. Sympathetic stimulation does not cause significant vasoconstriction of either cerebral or coronary vessels, with normal blood flow maintained in these circulations. Blood flow to the skin is sacrificed early, followed by that to the kidneys and splanchnic viscera.

The use of modified amino acid solutions is based on the false neurotransmitter hypothesis of the cause of hepatic coma. According to this hypothesis, the imbalance between aromatic and branched-chain amino acids in the plasma results in abnormally high levels of the toxic aromatic amino acids in the brain, thus provoking hepatic encephalopathy. The use of modified amino acid mixtures, with glucose as the calorie base, has been associated in a number of studies with improvement in encephalopathy. Meta-analysis has concluded that the use of such solutions is indicated as therapy for hepatic encephalopathy but has been proposed only for hepatic encephalopathy complicating acute exacerbation of chronic liver disease. Although there are a few anecdotal reports of beneficial effects on hepatic encephalopathy of acute fulminant hepatitis, the use of such a solution has not been advocated, but such a modified solution is tolerated better than standard amino acid mixtures in patients requiring TPN. In some studies, particularly in complicated surgical cases, the use of a high–branched-chain, low–aromatic amino acid solution has been associated with lower mortality. These statements are true only for studies in which the modified solutions are given with hypertonic glucose as a calorie base. Studies in which lipid was the principal calorie source have not revealed such improvements in mortality. In recent studies, giving an aromatic amino acid–deficient, branched-chain amino acid–enriched solution to patients about to undergo resection of the liver has proved particularly efficacious in a group of patients with cirrhosis, decreasing morbidity and showing a trend toward decreased mortality.

The causes of pulmonary edema are: 1) increased hydrostatic pressure; 2) increased capillary permeability and 3) decreased plasma oncotic pressure. The latter, however, is rarely a problem unless the concentration of plasma protein is very low. When fluid begins to collect in the lung interstitium, it migrates to the loose areolar portion of the lung microanatomy that surround the small bronchioles and pulmonary arteries. The edema in these areas has the effect of narrowing bronchi and increasing resistance in the pulmonary vasculature. This will decrease both ventilation and perfusion in the edematous area, but ventilation is often affected more than blood flow, resulting in a decreased / ratio, with all of its attendant effects on gas exchange. Ventilator treatment of pulmonary edema which increases airway pressure tends to hold the alveoli open, spreading out the space available for water accumulation and overcomes the effect of small bronchial occlusion. Positive pressure ventilation does not, therefore, affect the amount of edema in the lung, only its manifestations.

Few papers have excited as much interest as that by Askanazi, Kinney, and co-workers, which demonstrated that glucose calories given to patients with severe respiratory impairment may result in difficulty in weaning from a respirator. Subsequent research has suggested, however, that this occurs only with severe overfeeding, when the respiratory quotient is greater than 1 and calories are excessive. If one examines the conditions under which Askanazi's patients were studied, these were a group of septic, depleted patients who were taken from almost no nutritional support to a caloric supply of 2.25 times their caloric requirement, most of the calories consisting of glucose. Suffice it to say that, in patients with impaired respiratory function, one should measure VCO2 and, when VCO2 is significantly elevated and appears to interfere with weaning, decrease the amount of glucose calories and increase the amount of fat. If one measures or estimates calorie requirements and does not overfeed, lipid can be utilized for 25% of the caloric requirement and glucose for the remainder, without much fear of excessive CO 2 production.

Although peripheral access can be used for intravenous nutrition, the major disadvantage of this technique is limited caloric delivery to meet catabolic demands within tolerated fluid limits. Infusion of glucose (up to 10%), amino acid solutions, and fat emulsions can be administered peripherally but these solutions must be nearly isotonic to avoid peripheral vein sclerosis. The preferred method of access for total parenteral nutrition is into the superior vena cava by cutaneous cannulation of the subclavian vein. Alternative sites include the internal and external jugular vein but the catheter exiting from the neck region makes it more difficult to secure and maintain a sterile dressing. Complications from long-term central venous catheterization include venous thrombosis and venous catheter-related infection. Thrombosis of central vessels is a complication which is often overlooked. The clinical suspicion of subclavian vein thrombosis is only about 3%, whereas studies that use phlebography or radionucleotide venography indicate the incidence is as high as 35%.

Shock from cardiac compression occurs when external pressure on the heart impairs ventricular filling. Because ventricular filling is a function of venous return and myocardial compliance, any process that places pressure on the heart can cause compressive cardiogenic shock. Included among these are pericardial tamponade, tension pneumothorax, mediastinal hematoma, and positive pressure from mechanical ventilation. Any patient with hypotension after a wound in proximity of the heart should be considered to have compressive cardiogenic shock until proven otherwise. The classical clinical findings of pericardial tamponade include Beck’s triad of hypotension, neck vein distention and muffled heart sounds. Pulses paradoxus may be noted (this involves a decrease rather than the normal increase of systolic blood pressure with inspiration; values 10mmHg are significant). These findings, however, may be obscured in a noisy emergency room environment by positive pressure ventilation or by associated injuries. Placement of a CVP catheter confirms the elevation of right-sided filling pressure. If a pulmonary artery catheter has been placed, findings consistent with tamponade or other forms of cardiac compression are a trend toward equalization of chamber pressures as hypotension progresses. In the patient at risk, echocardiography is an extremely sensitive and noninvasive approach to demonstrate pericardial fluid and the need for operation. Pericardial tamponade must be relieved urgently and cardiac injuries require emergent sternotomy. Chest tube placement would not be appropriate as the sole treatment in this patient.

The role of nutritional support in the cancer patient remains an important component of overall therapy. Preoperative nutritional support should be given only to those patients who do not require an emergency operation and who have severe weight loss (> 15% of pre-illness body weight) and a serum albumen

Several important systemic factors or conditions influence wound healing. Interestingly, there are no known systemic conditions that lead to enhanced or more rapid wound healing. Overall nutrition as well as adequate vitamins play an important role in wound healing. Vitamin A is involved in the stimulation of fibroplasia, collagen cross-linking, and epithelialization. Although there is no conclusive evidence in humans, vitamin A may be useful clinically for steroid-dependent patients who have problematic wounds or who are undergoing extensive surgical procedures. Vitamin C is a necessary cofactor in hydroxylization of lysine and proline in collagen synthesis and cross-linkage. The utility of vitamin C supplementation in patients who otherwise take in a normal diet has not been established. Vitamin E is applied to wounds and incisions empirically by many patients. The evidence to support this practice is entirely anecdotal. In fact, large doses of vitamin E have been found to inhibit wound healing. Zinc and copper are also important cofactors for many enzyme systems that are important to wound healing. Deficiency states are seen with parenteral nutrition but are rare and readily recognized and treated with supplements. Overall, vitamin and mineral deficiency states are extremely rare in the absence of parenteral nutrition or other extreme dietary restrictions. There is no evidence to support the concept that supranormal provision of these factors enhance wound healing in normal patients.

The kidney is extremely sensitive to changes in serum bicarbonate concentration and responds by increasing net acid excretion primarily by increasing ammonia excretion. Maximal renal compensation requires 2 to 4 days. Delay in achieving maximal renal response to an increased acid load causes blood pH to decline, which stimulates hyperventilation. Although effective in promptly raising blood pH, ventilatory compensation is only partial, and full respiration compensation requires 12 to 24 hours. The major principal of treatment for mild to moderate acute metabolic acidosis is correction of the underlying cause. In surgical and trauma patients, metabolic acidosis is often the result of hypoxia secondary to inadequate tissue perfusion and subsequent lactic acidosis. Volume and/or blood resuscitation alone may be enough to correct the acidosis. Attempts to correct acidosis with exogenous bicarbonate before correction of inadequate tissue perfusion are usually unsuccessful. The use of bicarbonate for the treatment of lactic acidosis is controversial at best. In several studies the use of bicarbonate in patients with lactic acidosis does not improve clinical parameters or outcome. The correction of both acidosis and hypoglycemia of diabetic ketoacidosis is best achieved by the administration of insulin. Volume resuscitation is also required. Potassium replacement is essential, even in the face of normal or high serum potassium, and as hypokalemia develops as acidosis in hyperglycemia are corrected

Glutamine is the most studied gut-specific nutrient. Glutamine has been classified as a nonessential or nutritionally dispensable amino acid since glutamine can be synthesized in adequate quantities from other amino acids and precursors. Glutamine is not included in most nutritional formulas and has been eliminated from TPN solutions because of its relative instability and short half life compared to other amino acids. With few exceptions, glutamine is present in oral enteral diets but only at relatively low levels characteristic of the concentration in most animal and plant stores (about 7% of total amino acids). Several recent studies, however, have demonstrated that glutamine may be an essential amino acid during critical illness, particularly as it relates to supporting the metabolic requirements of the intestinal mucosa. These studies demonstrate that dietary glutamine is not required during states of health but appears to be beneficial when glutamine depletion is severe and/or when intestinal mucosa is damaged by insults such as chemotherapy or radiation therapy. The addition of glutamine to enteral diet reduces the incidence of gut translocation but these improvements are dependent upon the amount of supplemental glutamine and the type of insult studied. Glutamine-enriched TPN partially attenuates villous atrophy that develops during parenteral nutrition. The use of intravenous glutamine in patients appears to be safe and effective in its ability to maintain muscle glutamine stores and improve nitrogen balance. In contrast to glutamine, short chain fatty acids are primary energy source for colonocytes.

The use of empiric therapy without the benefit of well-defined microbiologic data is appropriate when there is sufficient clinical evidence to support the diagnosis such that it would be imprudent to withhold antimicrobial therapy. In this setting, however, a diligent search for the septic focus source should be undertaken and continued (cultures, radiographic procedures, etc.), and initial limits should be placed in the course of empiric therapy with continued reevaluation based on the clinical course of the patient. The choice of antibiotic agents should be based on the clinical situation and known activity patterns within the given institution. Single broad-spectrum agents, although suffering slightly from a lack of individual pathogen specificity, are useful in this setting in that they provide a broad coverage against several groups of pathogens and may avoid some of the toxic effects with specific combined modality regimens. Similarly, for directed therapy, single-agent therapy has been demonstrated to be equivalent to combined therapy and should be chosen in an attempt to select agents with appropriate sensitivities which retain suitable clinical efficacy but exhibit minimal toxicity. After review of cultural reports, many patients have demonstrated polymicrobial infection. Because experimental clinical evidence supports the concept of aerobic-anaerobic synergy, therapy should be directed against all potential components of the infection if the body site is such that these microorganisms may be present.

Hypovolemic shock is readily diagnosed when there is an obvious source of volume loss and overt signs of hemodynamic instability and increased adrenergic output are present. After acute hemorrhage, hemoglobin and hematocrit values do not change until compensatory fluid shifts have occurred or exogenous fluid is administered. These values decrease once transcapillary refill, osmotic-induced shifts, or non-RBC volume resuscitation expands the blood volume. It is imperative that the distinction be made between hypovolemic and cardiogenic forms of shock, because appropriate therapy differs dramatically. Restoration of perfusion in hypovolemic shock requires reexpansion of circulating blood volume in conjunction with necessary interventions to control ongoing volume loss. Continued hemodynamic instability after fluid resuscitation implies that shock has not been reversed or that there is ongoing blood or volume loss. In severe, prolonged hypovolemia, ventricular contractile function may itself become depressed and require inotropic support to maintain ventricular performance, but in general, pharmacologic interventions directed toward increased contractility in situations of inadequate preload are ineffective, further complicate metabolic derangements, and are not indicated until adequate volume replacement has been completed. Complications are less frequent after treatment of hemorrhagic shock than in situations of septic or traumatic shock. In the later circumstances, the massive activation of inflammatory mediator response systems and consequences of their disseminated, indiscriminate cellular injury can be quite profound.

Selective gut decontamination involves the use of orally administered antibiotics that achieve a high intraluminal level directed against gram-negative aerobes and yeast, leaving the host anaerobic intestinal microflora relatively undisrupted. Although a reduction and alteration of the microorganisms responsible for infectious episodes have been demonstrated in certain groups of patients, a clear-cut impact on host mortality has not been shown. Because LPS may be responsible for toxicity both directly and through host mediator systems, the availability of agents to bind against this portion of the gram-negative bacteria to reduce mortality has been intensively examined. Unfortunately, large multicenter randomized trials provide no evidence of benefit for this treatment. Similarly, since many of the systemic manifestations of gram-negative bacteremia are mediated by cytokines, the effect of an anti-TNF antibody preparation is currently in clinical trial. No proven benefits have yet been identified. Finally, the use of immunostimulants to enhance the state of activation of host defenses has been proposed. Thymopentin is a peptide that contains active thymopoetin, a thymic molecule that acts to stimulate T-lymphocyte activity. Preliminary trials indicate that this agent ameliorates host septic response after major operations and trauma but conclusive evidence that concurrent reduction of infection-related mortality occurs is not available.

Inflammatory mediators have recently been recognized as playing a significant role in the clinical manifestations and progression of shock and the development of subsequent complications. These mediator systems function primarily as parcrine and autocrine agents in the local environment and are not usually detectable systemically. The over-expression and systemic dissemination of these mediators produces the toxic autodestructive processes underlying multiorgan failure syndrome with attendant high mortality. The compliment cascade is activated in shock and tissue injury through both the classical and alternative pathways. Activation of either pathway results in generation of the anaphylatoxin, C3a and C5a, soluble products with potent systemic hemodynamic effects. The eicosanoids, which include the prostaglandins and leukotrienes are formed acutely from arachidonic acid released from the membrane phospholipid by phospholipase A2. Eicosanoids are not stored in any measurable level and are generated as needed from readily available arachidonic acid in response to various inflammatory phenomena. Platelets, white cells, and endothelial cells are a rich source of these compounds. Thromboxane (TXA2) is the major arachidonic acid metabolite elaborated by platelets. TXA2 induces intense vasoconstriction, platelet aggregation and degranulation, neutrophil margination in the microcirculation and bronchial constriction. PGI2, the major arachidonic acid metabolite formed by endothelial cells, serves a check against actions of TXA2. PGI2 is a vasodilator and a potent inhibitor of platelet aggregation. Platelet aggravating factor is a potent phospholipid mediator released by neutrophils, platelets, macrophages and endothelial cells in response to ischemia, tissue injury and sepsis. Its effects include decreased cardiac function, increased pulmonary vascular resistance, bronchoconstriction, peripheral vasodilatation, and increased vascular permeability.

IL-1 and TNFa share many biologic properties. In addition, each potentiates the effects of the other one when given concurrently. Overall, IL-1 alone probably has weaker effects than TNFa with respect to the induction of shock; its role is likely to be important with respect to its marked potentiating abilities as it relates to TNFa. IL-1 expression is regulated by a host of factors including IL-2, granulocyte macrophage colony stimulating factor (GM-CSF), transforming growth factor b (TGF-b), TNFa, all of the interferons, and IL-1 itself. Other endogenous stimuli for IL-1 production include antigen-antibody complex, the Fc region of IgG, and C5a; other nonspecific exogenous stimuli include silica particles and UV irradiation.
One of the key proinflammatory features of IL-1-induced inflammation is the stimulation of arachadonic acid metabolism. IL-1 stimulates the release of pituitary stress hormones and increases the synthesis of collagenases, resulting in the destruction of cartilage, bone and other collagen-rich structures. IL-1 stimulates prostaglandin production.
One of the most important properties of IL-1 involves its interaction with the vascular endothelium. This includes the adherence of neutrophils, basophils, eosinophils, monocytes, and lymphocytes to the vascular endothelium via interaction between adhesion molecules on leukocytes and adhesion-receptor complex on the endothelial cells. By inducing the expression of ICAM-1, E-selectin, and VCAM-1 on endothelial cells, IL-1 provides a key step in the extravasation of leukocytes to sites of local inflammation and injury.

Total body water (TBW) is distributed within the intracellular and extracellular compartments. Intracellular fluid cannot be measured directly but is calculated as the difference between TBW and the measured extracellular water. Extracellular fluid can be measured directly. The extracellular fluid compartment can be further simplified into the intravascular and interstitial spaces. Intravascular space, which accounts for 20% of the extracellular fluid, contains the plasma volume which is approximately 8% of TBW or 5% of body weight. The interstitial space extends from the blood vessels to the cells themselves and includes the complex ground substance making up the acellular matrix of tissue. Although the water within the space is thought to be freely exchangeable, this water exists in two phases. The free phase contains water that is generally freely exchangeable and in a constant state of flux. The bound or gel phase is composed of water that is closely associated with glycosaminoglycans, mucopolysaccharides, and other matrix components. This water is much less freely exchangeable. An additional extracellular fluid compartment, the transcellular compartment, consists of water that is poorly exchangeable under normal circumstances. This fluid is separated from other compartments by both endothelial and epithelial barriers and includes cerebrospinal fluid, synovial fluid, water within cartilage and bone, fluids of the eye, and the lubricating fluids of the serous membranes. Together, these fluids constitute about 4% of TBW.

Narcotics and synthetic analogues belong in the class of drugs called opioids. Narcotics produce profound analgesia and respiratory depression. They have no amnesic properties, no myocardial depressive effects, and no muscle relaxant properties. Narcotics may produce significant hemodynamic effects indirectly through the release of histamine and/or blunting of the patient’s sympathetic vascular tone due to analgesic properties. Acutely injured patients may be hypovolemic and in pain, with high sympathetic tone and peripheral resistance. Therefore, such patients can experience a dramatic drop in systemic blood pressure with minimal doses of opioids. All opioids can be reversed with naloxone. Naloxone reversal, however, can be dangerous because the agent acutely reverses not only the analgesic effects of the opioid but also analgesics effects of native opioids. Naloxone treatment has been associated with acute pulmonary edema and myocardial ischemia and should not be used electively to reverse the effects of narcotic. Propofol is a lipid-soluble substitute isopropyl phenol non-narcotic agent that produces rapid induction of anesthesia followed by awakening in four to eight minutes.

Neurogenic shock results from interruption of sympathetic vasomotor input and develops after spinal cord injury, spinal anesthesia, and severe head injury. Under normal conditions, baseline sympathetic activity establishes a degree of arteriolar and venous constriction. Ablation of this tone results in decreased systemic vascular resistance and a dramatic increase in venous capacity, causing hypotension due to relative hypovolemia. Arteriolar dilatation not only lowers the systemic vascular resistance but also allows previously unopened vascular beds to be perfused, greatly expanding venous capacity. Removal of sympathetic inputs to innervated portions of the venous system allows further venodilatation. Restoration of an effective, albeit expanded, intravascular volume may require extremely large volumes of resuscitation fluid to restore normal cardiac filling pressures. This will restore cardiac output and reverse hypotension. However, pharmacologic intervention with vasoactive drugs may be necessary and is preferable to excessive volume resuscitation. Post-shock sequelae are infrequent. Although there is significant hypotension with neurogenic shock, there is usually little if any hypoperfusion. Thus, activation of inflammatory cascade and subsequent organ injury rarely occur.
A major pitfall in the management of neurogenic shock arises when there is coexistent hemorrhage or ongoing volume loss that is not appreciated. This is not an unusual situation because cervical spine trauma causing paraplegia or severe head injury is frequently associated with multiple injuries. Thus, in trauma the initial response to neurogenic shock is large volume resuscitation regardless of the presumed etiology. If hemodynamic instability persists after initial trauma resuscitation, one must assume that the cause is not neurogenic and search for occult blood loss or cardiogenic causes of shock.